May 12, 2003

Oversight

With a little bit of training--and a few peanuts--a monkey could probably learn to give a flu shot. It is a breathtakingly anti-climactic process: You pick up a syringe prefilled with a droplet of the inoculum, flick the bubbles out, then jab the contents into the shoulder of a patient. The procedure takes just seconds, requires almost no dexterity, and demonstrates no particular skills. It is, in short, one of the least complicated tasks in all of medicine--and perhaps the least glamorous. No one ever gets a flu shot on "ER."

But it's what precedes that pinprick that makes flu vaccinations one of the most complex of all human activities. To start with, the virus itself is infernal. Influenza--unlike, say, hepatitis B or smallpox--mutates at a furious pace every year. As a result, the vaccine, like a fussy piece of clothing, needs to be refitted each time to match its target. That, in turn, demands an astonishing international infrastructure--110 National Influenza Centers spread across 83 countries--to keep track of emerging strains of the flu. The influenza vaccine is thus built on a notion of perpetual vigilance--a concept called "integrated surveillance"--that involves laboratories, physicians, scientists, and field workers all over the world.

That phrase, integrated surveillance, is worth remembering because it went globally missing this year. Between November and April, as the lethal respiratory illness called SARS (severe acute respiratory syndrome) brewed furtively in Guangdong Province, public health experts outside China remained completely oblivious to the looming threat. The Chinese government obviously played a major role in suppressing the news: At least 305 cases were documented between November and February in Guangdong and neighboring provinces without any alarms being activated. But the unfortunate truth is that no one was really listening for alarms: The World Health Organization (WHO), the agency most likely to have heard them, had no functional surveillance program for emerging diseases in place.

The irony is that the blueprint for such a surveillance system was staring the WHO in the face. The organization's influenza program and its similarly structured international anti-polio effort have both been humming away since the 1950s. Between November and April, flu centers and polio centers all over the world--in Ankara and Mumbai and Atlanta--continued to log in data with meticulous precision. The influenza Web server, called Flunet, registered thousands of reports from these centers and made detailed predictions about this year's flu epidemic. In other words, the tools needed to design a more general surveillance system--something that could have caught SARS early--were already in place. But, for all their success against polio and the flu, these tools had not yet been applied to the possibility of other emerging diseases. And, by the time the alarm bells started ringing at the WHO, it was too late.

The idea of a broader system of integrated surveillance--that someone should be actively trawling the world looking for emerging infectious diseases--isn't new. In 1994, nearly a decade before SARS, medical writer Laurie Garrett made a strong case for such a network. Garrett's book The Coming Plague analyzed 14 newly emerging infectious diseases--Ebola, Legionnaires' disease, and HIV among them. Near the end of her 700-page tome, in a chapter subtitled "Preparedness, Surveillance, and the New Understanding," Garrett argued that, while looking for known diseases, such as influenza or polio, was an essential part of the public health agenda, it was unlikely to be enough. "If a novel epidemic appeared," Garrett asked, "was the international public health community prepared to handle" it? Garrett concluded emphatically that it wasn't and that a network designed to capture the outbreak of such novel diseases was desperately needed.

In January 2000, these arguments began to register within the WHO. In an article in Weekly Epidemiological Record (the WHO's international bulletin), the authors seconded Garrett's proposal, pointedly noting that a global surveillance service for "emerging" diseases was clearly missing. "Effective communicable diseases control relies on effective response systems," the piece noted, "and effective response systems rely on effective disease surveillance." The article demolished any hope that current systems of vigilance, such as those implemented by national governments, would have any effect. "Some are effective," the authors concluded, but others "have lost momentum, are poorly maintained or have virtually collapsed." What the Record piece proposed instead was a "paradigm shift" in disease surveillance. And the authors made three concrete suggestions that, in retrospect, could have had a profound impact on the SARS outbreak.

The first idea was that, like the anti-flu and anti-polio efforts, a system for combating emerging diseases should be "integrated" (i.e., centralized) so doctors in disparate parts of the globe--Mongolia and Madagascar, say--could watch out for clusters of disease and warn each other of impending epidemics.

In January 2000--ironically, the very month that the Record made its case for global surveillance--the success of the influenza survey system was put on full display in Europe and the United States. By mid-January that year, Europe had already begun to reel under the threat of a severe influenza epidemic. Between October 1999 and February 2000, the WHO (collaborating with the European Influenza Surveillance Scheme) pooled data from nearly 700,000 patients in England, 305,000 in Portugal, and 112,371 in Spain. Flu-watchers surveyed 3,500 general practitioners in the Czech Republic, 550 in Germany, and 376 in France. All in all, data from well over one million patients in eleven countries was meticulously entered and analyzed. Doctors, field workers, and scientists were mobilized. Swabs were shipped off to the influenza centers, the virus was genotyped, and laboratories briskly started working on a new vaccine for the coming winter.

At first glance, the findings of the group seemed predictable enough: The major strain of influenza circulating through Europe, called H3N2, was an old and familiar culprit. H3N2 had been active in the United States for the last five flu seasons, and its reemergence in Europe was no surprise. But hidden within the larger European epidemic was a rarer, more sporadic strain of influenza, a virus called H1N1. Such mutational gymnastics--a flu buried within a flu--are precisely the sort of thing the influenza network was designed to thwart. As a result of the discovery, in March 2000, the WHO's recommendation for the North American vaccine for 2000-2001 was a "mixture" comprising H3N2 and H1N1 and a third, even rarer strain of the flu that had been circulating in Asia.

That winter, the fear of a lethal influenza epidemic gripped Boston. In a windowless clinic on the sixth floor of my hospital, I spent several mornings giving patients the newest version of flu vaccine. Elderly men and women nearly clogged the hospital corridors every morning waiting for their flu shot. And, true to form, on December 5, 2000, the first case of influenza was suddenly upon us: A five-year-old child was diagnosed with a mild case in Boston. From that day onward, there was a steady rise in cases. The flu hovered tentatively over Boston and New York, threatening to overwhelm hospital emergency rooms and wards. At least two of my patients--an 80-year-old woman from South Boston and a middle-aged man who smoked incessantly--almost died from it.

And then, all of a sudden, it was gone. When the flu strain for the sick five-year-old, along with thousands of subsequent cases, was analyzed and genotyped, it turned out to be H1N1, the rarer strain that the WHO had included in its recommended vaccine for that year. It's hard to know whether the U.S. flu was milder than the European flu because of the prescient choice of that vaccine. But what influenza 2000 did prove, once again, was that the surveillance system "worked," that it was extremely efficient in identifying circulating viruses long before they could unleash deadly epidemics.

But all this seems easy enough to do with the flu. Influenza, like polio, is a well-defined disease, with its own lab tests and diagnostic criteria. In the case of SARS, however, there was no well-defined disease to start with. Even medical journals were initially baffled by the illness. How then could the WHO have created a "surveillance system" for a disease that hadn't even been named?

The Record piece addressed this problem with its second suggestion. The trouble with the old systems, the authors argued, was that they were only mechanisms of recording known diseases. What was needed was a method by which the WHO could catch any disease that might emerge within a finger's reach of one of its survey centers. What the WHO needed was not only an integrated system but also a new way of recording data on diseases.

In mid-April, a few weeks into the SARS crisis, I asked Cyrus Hopkins, an infectious-disease expert at Massachusetts General Hospital, whether a global surveillance system could possibly capture a hitherto unknown disease. Hopkins is a tall, 60-something physician with a shock of white hair and a perpetual open-toothed smile. During his tenure as a doctor, he has hunted down malaria in Pakistan and run anthrax simulations for the U.S. government. If anyone knew the frustrations of disease surveillance, I imagined, it would be Hopkins.

Hopkins's answer to the problem turned out to be another throwback to the early days of mass vaccinations. "Those polio experts knew about this problem all along," he said. "Way back when, in the 1960s or so, they had figured out a system. They switched to recording syndromes instead of diseases. That way, the field doctors could just describe what they had seen--and the rest could be left to the labs."

It is a brilliantly simple approach--and, again, one that has been used with the flu. For the WHO's influenza tracking system, doctors need only report a cluster of symptoms--fevers, muscle pain, breathing troubles, and so on--that would classify a disease as an ILI, or an influenza-like illness. Swabs from ILIs are sent off to a centralized site and further characterized there. By the early '80s, the flu-watchers had become even more crafty: They began to track rises in visits to general practitioners as the earliest marker for an impending influenza outbreak. This process--of initially charting a disease through its telltale signs and symptoms, rather than laboratory tests or confirmed diagnoses--even has its own moniker: "syndromic" monitoring.

Could syndromic monitoring have picked up SARS? There's good reason to think that it might have. Even if doctors often don't know what to call a new illness, they generally do know when something is deeply wrong. In San Francisco in the mid-'80s--long before HIV had a name--doctors began to suspect that something wasn't quite right with the bizarre infections that were sprouting up among gay men. So, too, with SARS: On February 21, Dr. Liu Jianlun, a lung specialist from Zhongshan Hospital, checked himself into a Hong Kong hospital with fever, chills, and labored breathing. Jianlun didn't know exactly what was wrong with him, but he knew that it wasn't simply any old pneumonia. As a result, Jianlun advised doctors and nurses to put on masks and gloves when they examined him. His instinct proved right: Within a week, the lung doctor was dead from SARS, the first such case to be described in Hong Kong.

That instinct is one of the most fundamental--and powerful--in all of medicine. Stripped of all its complex technical content, medicine is frequently made up of such instincts, gut feelings that allow doctors to distinguish the normal from the abnormal, to listen for subtle signals in the noise, to look for patterns within scattered points. It is gossip mixed with wisdom, dressed up in a white coat.

If syndromic monitoring is so effective, why didn't the WHO use the concept for other diseases much earlier? Because monitoring syndromes can be a frustrating and expensive business. It was deployed so effectively against polio because polio causes unique symptoms: Not many diseases cause "acute flaccid paralysis," the syndrome characteristically associated with it. If doctors had to report every single outbreak of respiratory illnesses, however--if every cough and sneeze foreboded a deadly epidemic--the WHO would soon be drowning in data. Over the course of the winter, tens of thousands of such cases check into hospitals around the world every week; only the tiniest fraction of these will end up being diseases worth monitoring.

But, whatever the general problems with this approach, it could have worked quite well for SARS. The SARS "syndrome," after all, wasn't subtle: Doctors in Guangdong and Hong Kong knew there was something odd about the hundreds of patients with aggressive, multifocal pneumonias who suddenly seemed to drop dead in their intensive care units. The gossip and wisdom that these findings must have generated was certainly suppressed by the Chinese government. But, had an animated, pervasive syndromic-monitoring unit been on the lookout, it might have registered unusual death notices in Guangdong or even picked up rumors from hospitals in Beijing. These hazy forebodings might have tipped off public health officials around the world. And, if international authorities had known about SARS a month earlier, they might have issued a quarantine in and around Guangdong Province and warned health care workers about the potential risks. That, in turn, might have prevented the epidemic's spread to faraway nations, such as Singapore, Australia, and Canada.

The third and final point made by the Record piece was perhaps the thorniest: Because local surveillance authorities were already moribund, it was time to replace them with more efficient, international systems.

The failure of local networks to relay information adequately became apparent in the course of the SARS crisis. Early this year, as new cases of pneumonia began to mushroom in Shunde and Heyuan, local hospitals tried desperately to convince Guangdong authorities that a new disease was on the loose. But no health alert was issued. As The New York Times pointed out last week, "It was unclear whether [the] conclusion was passed on by provincial officials to the Ministry of Health." In other words, SARS proved a principle of epidemiology that Hopkins had referred to during his conversation with me: Local knowledge is often plentiful; it's local surveillance that is often missing.

Converting knowledge into surveillance obviously requires political support. And a key question is whether secretive and imperious governments, such as China's, will ever allow the WHO to create permanent outposts within their borders. Part of the answer, again, lies in the influenza experience. So far, the Chinese government has allowed two influenza centers (in Beijing and in Hong Kong) to exist for more than a decade without much resistance. That may have been driven by self-interest: Like SARS, influenza has a disproportionate effect on China. And the economic and political burdens of both epidemics are likely to presage important changes for the future. Amir Attaran, a public health specialist who studies international public health at the Kennedy School of Government at Harvard, certainly hopes this will happen. "It always comes down to the economic pinch," he told me. "The impact of large epidemics, such as HIV, is denied by governments at first." He added: "It wouldn't be surprising if SARS took out 0.5 percent of the Chinese growth rate for this year. That would certainly make them sit up and pay attention."

That economic pinch, if it gets severe enough, might create a unique opportunity for the WHO to peddle its plans for a global surveillance network to wealthy governments. Like influenza, but unlike most infectious diseases, SARS has found its way into developed nations such as Canada, Australia, and the United States. And that, in turn, might persuade these nations to pitch in some money toward a global surveillance effort that would be otherwise difficult to fund. To some extent, this effort could use the infrastructure already created by the influenza network. Some of the resources used so effectively by the flu-watchers--records of visits to general practitioners, access to hospital databases, a powerful Web server tended by hundreds of epidemiologists--could even be adopted by the surveillance network.

If the political will and financial support can be mustered through international campaigns, then the onus would shift to the WHO. And, to be fair, the organization has been moving in this direction already: Between 2000 and 2003, it piloted eight projects in Africa focusing on disease surveillance. These projects were tiny compared with the influenza or polio efforts. But the point is that these projects don't need to be "pilots" for very long: A functional and successful model for surveillance already exists, and it has already had a powerful impact on other major human epidemics. It is probably a good rule of public health that those who ignore the history of old epidemics are cursed to repeat them. Before SARS, ignoring that axiom might have been shortsighted. After this winter's experience, ignoring it will be unconscionable.

Siddhartha Mukherjee is a senior resident in internal medicine at Massachusetts General Hospital and a clinical fellow at Harvard Medical School.